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Pancreatic Neoplasms: HELP
Articles by Dr. J Berlin
Based on 35 articles published since 2008
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Between 2008 and 2019, J. Berlin wrote the following 35 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Consensus statement on mandatory measurements in pancreatic cancer trials (COMM-PACT) for systemic treatment of unresectable disease. 2018

Ter Veer, Emil / van Rijssen, L Bengt / Besselink, Marc G / Mali, Rosa M A / Berlin, Jordan D / Boeck, Stefan / Bonnetain, Franck / Chau, Ian / Conroy, Thierry / Van Cutsem, Eric / Deplanque, Gael / Friess, Helmut / Glimelius, Bengt / Goldstein, David / Herrmann, Richard / Labianca, Roberto / Van Laethem, Jean-Luc / Macarulla, Teresa / van der Meer, Jonathan H M / Neoptolemos, John P / Okusaka, Takuji / O'Reilly, Eileen M / Pelzer, Uwe / Philip, Philip A / van der Poel, Marcel J / Reni, Michele / Scheithauer, Werner / Siveke, Jens T / Verslype, Chris / Busch, Olivier R / Wilmink, Johanna W / van Oijen, Martijn G H / van Laarhoven, Hanneke W M. ·Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Department of Internal Medicine III, Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany. · Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France. · Royal Marsden NHS Foundation Trust, London and Surrey, UK. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Gastroenterology and Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium. · Department of Oncology, Hôpital Riviera-Chablais, Vevey, Switzerland. · Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Nelune Cancer Centre, Prince of Wales Hospital, Prince of Wales Clinical School University of New South Wales, Randwick, NSW, Australia. · Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. · Cancer Center, ASST Papa Giovanni XXIII, Bergamo, Italy. · Department of Gastroenterology, Gastrointestinal Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Vall d'Hebron University Hospital (HUVH), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. · Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. · Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine I, Medical University Vienna, Vienna, Austria. · Division of Solid Tumor Translational Oncology, West German Cancer Cancer, University Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Digestive Oncology, University Hospitals Leuven, Leuven, Belgium. · Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, Netherlands. Electronic address: h.vanlaarhoven@amc.uva.nl. ·Lancet Oncol · Pubmed #29508762.

ABSTRACT: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.

2 Guideline Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. 2017

Khorana, Alok A / Mangu, Pamela B / Berlin, Jordan / Engebretson, Anitra / Hong, Theodore S / Maitra, Anirban / Mohile, Supriya G / Mumber, Matthew / Schulick, Richard / Shapiro, Marc / Urba, Susan / Zeh, Herbert J / Katz, Matthew H G. ·Alok A. Khorana and Marc Shapiro, Cleveland Clinic, Cleveland, OH · Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA · Jordan Berlin, Vanderbilt University, Nashville, TN · Anitra Engebretson, Pancreatic Cancer Action Network, Manhattan Beach, CA · Theodore S. Hong, Massachusetts General Hospital, Boston, MA · Anirban Maitra and Matthew H.G. Katz, The University of Texas MD Anderson Cancer Center, Houston, TX · Supriya G. Mohile, University of Rochester, Rochester, NY · Matthew Mumber, Harbin Clinic, Rome, GA · Richard Schulick, University of Colorado at Denver, Denver, CO · Susan Urba, University of Michigan, Ann Arbor, MI · and Herbert J. Zeh, University of Pittsburgh, Pittsburgh, PA. ·J Clin Oncol · Pubmed #28398845.

ABSTRACT: Purpose To update the Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline published on May 31, 2016. The October 2016 update focuses solely on new evidence that pertains to clinical question 4 of the guideline: What is the appropriate adjuvant regimen for patients with pancreatic cancer who have undergone an R0 or R1 resection of their primary tumor? Methods The recently published results of a randomized phase III study prompted an update of this guideline. The high quality of the reported evidence and the potential for its clinical impact prompted the Expert Panel to revise one of the guideline recommendations. Results The ESPAC-4 study, a multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy compared gemcitabine and capecitabine with gemcitabine monotherapy in 730 evaluable patients with resected pancreatic ductal adenocarcinoma. Median overall survival was improved in the doublet arm to 28.0 months (95% CI, 23.5 to 31.5 months) versus 25.5 months (95% CI, 22.7 to 27.9 months) for gemcitabine alone (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = .032). Grade 3 and 4 adverse events were similar in both arms, although higher rates of hand-foot syndrome and diarrhea occurred in patients randomly assigned to the doublet arm. Recommendations All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The doublet regimen of gemcitabine and capecitabine is preferred in the absence of concerns for toxicity or tolerance; alternatively, monotherapy with gemcitabine or fluorouracil plus folinic acid can be offered. Adjuvant treatment should be initiated within 8 weeks of surgical resection, assuming complete recovery. The remaining recommendations from the original 2016 ASCO guideline are unchanged.

3 Guideline Pancreatic adenocarcinoma. 2010

Tempero, Margaret A / Arnoletti, J Pablo / Behrman, Stephen / Ben-Josef, Edgar / Benson, Al B / Berlin, Jordan D / Cameron, John L / Casper, Ephraim S / Cohen, Steven J / Duff, Michelle / Ellenhorn, Joshua D I / Hawkins, William G / Hoffman, John P / Kuvshinoff, Boris W / Malafa, Mokenge P / Muscarella, Peter / Nakakura, Eric K / Sasson, Aaron R / Thayer, Sarah P / Tyler, Douglas S / Warren, Robert S / Whiting, Samuel / Willett, Christopher / Wolff, Robert A / Anonymous3820673. · ·J Natl Compr Canc Netw · Pubmed #20876541.

ABSTRACT: -- No abstract --

4 Editorial Timing versus duration of adjuvant therapy for pancreatic cancer: all the lessons we need in life are taught to us as children. 2014

Chan, Emily / Berlin, Jordan. ·Vanderbilt University Medical Center, Nashville, TN. ·J Clin Oncol · Pubmed #24419124.

ABSTRACT: -- No abstract --

5 Editorial Pancreas cancer on the rise: are we up to the challenge? 2013

Cardin, Dana B / Berlin, Jordan D. ·Affiliation of authors: Department of Medicine, Vanderbilt University, Nashville, TN. ·J Natl Cancer Inst · Pubmed #24203986.

ABSTRACT: -- No abstract --

6 Editorial Editorial: Combined modality treatment of resectable and borderline resectable pancreas cancer: expert consensus conference. 2009

Berlin, Jordan / Hoffman, John P / Regine, William F. · ·Ann Surg Oncol · Pubmed #19396493.

ABSTRACT: -- No abstract --

7 Editorial Past and future of pancreas cancer: are we ready to move forward together? 2008

Merchant, Nipun / Berlin, Jordan. · ·J Clin Oncol · Pubmed #18640927.

ABSTRACT: -- No abstract --

8 Review Current Concepts in the Treatment of Resectable Pancreatic Cancer. 2018

Roth, Marc T / Berlin, Jordan D. ·Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN, 37212, USA. marc.roth@vanderbilt.edu. · Department of Internal Medicine, Vanderbilt University Medical Center, 1211 Medical Center Dr, Nashville, TN, 37212, USA. · Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Curr Oncol Rep · Pubmed #29582218.

ABSTRACT: PURPOSE OF REVIEW: The diagnosis of pancreatic cancer carries with it a high mortality rate. Despite advances in the field, this has remained relatively unchanged over the last few decades. Current options for the treatment of resectable pancreatic ductal adenocarcinoma will be reviewed here in conjunction with the historical data that support them. We will focus on updates in treatment guidelines and ongoing clinical trials of interest. RECENT FINDINGS: For localized disease, standard of care includes resection followed by adjuvant chemotherapy ± chemoradiation. Recently, a report was published supporting the use of doublet therapy with gemcitabine and capecitabine (as opposed to gemcitabine monotherapy), which prompted a practice-changing update to major treatment guidelines. Multiple trials using neoadjuvant treatment, novel therapies, and different forms of radiation are ongoing. Although pancreatic cancer is an active area of research, outcomes remain dismal. Clinical trials will need to be more robust and innovative to drastically improve survival statistics.

9 Review Preclinical Rationale for the Phase III Trials in Metastatic Pancreatic Cancer: Is Wishful Thinking Clouding Successful Drug Development for Pancreatic Cancer? 2017

Thota, Ramya / Maitra, Anirban / Berlin, Jordan D. ·From the *Division of Hematology/Oncology, Vanderbilt University, Nashville, TN; and †Sheikh Ahmed Pancreatic Cancer Research Center, Departments of Pathology and Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX. ·Pancreas · Pubmed #28085753.

ABSTRACT: Prior phase III trials in advanced pancreatic cancer have been predominantly unsuccessful. In this review, we attempt to understand how past preclinical data were translated into phase III clinical trials in metastatic pancreatic cancer as described in the article. A systematic literature review conducted through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, from January 1997 to June 2015 using key words-phase III clinical trials, metastatic/advanced pancreatic adenocarcinoma or pancreatic cancer identified 30 randomized controlled trials (RCTs) that met criteria. The trials were limited to RCTs in the first-line treatment of patients with metastatic pancreatic cancer. The success rate of first-line phase III studies in advanced pancreatic cancer was only 13%. In 60% of the RCTs, no preclinical experiments were referenced in biologically cognate pancreatic models. Nine (30%) of the RCTs were designed based on preclinical evidence from in vitro cell lines alone without additional in vivo validation in xenograft models. It remains uncertain how strongly the preclinical data influence the development of clinical regimens but so far the studies developed based on more solid preclinical evidence have been successful.

10 Review Evaluation of Pancreatic Cancer Clinical Trials and Benchmarks for Clinically Meaningful Future Trials: A Systematic Review. 2016

Rahib, Lola / Fleshman, Julie M / Matrisian, Lynn M / Berlin, Jordan D. ·Pancreatic Cancer Action Network, Manhattan Beach, California. · Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. ·JAMA Oncol · Pubmed #27270617.

ABSTRACT: IMPORTANCE: Progress in the treatment of pancreatic adenocarcinoma has been minimal; it remains the only major cancer type with a 5-year survival rate of less than 10%. OBJECTIVE: To explore why a large proportion of advanced pancreatic cancer clinical trials executed over the past 25 years have had negative results and to identify benchmarks that could have predicted success. EVIDENCE REVIEW: Phase 3 studies of patients with advanced pancreatic cancer were identified by searching clinicaltrials.gov and the scientific literature. FINDINGS: Thirty-two phase 3 studies in 13 675 chemotherapy-naive patients resulted in 3 agents or combinations being considered clinically meaningful. Nineteen agents or combinations (70%) were tested in phase 2 trials preceding the phase 3 trial. In cases with paired phase 2 and 3 results, meeting the primary end point of the phase 2 trial predicted the outcome of the phase 3 trial 76% of the time but proceeded despite phase 2 negative results in 10 cases. We applied criteria for a clinically meaningful result identified by the American Society of Clinical Oncology (ASCO) Cancer Research Committee to these historical cases. Overall, progression-free and 1-year survival of experimental arms was compared with time period-controlled median values of control arms to normalize for the observed increase in response to gemcitabine over time. CONCLUSIONS AND RELEVANCE: Applying the benchmark of a 50% improvement in overall survival as the primary end point to phase 2 data, or secondary end points of a 90% increase in 1-year survival or an 80% to 100% increase in progression-free survival, showed the greatest ability to predict a clinically meaningful phase 3 trial. Had these criteria been applied to these trials over the past 25 years, more than 11 571 patients enrolled in phase 3 trials that did not meet the primary end point could theoretically have been diverted to earlier-stage trials in an attempt to more rapidly advance the field.

11 Review The Past, Present, and Future of Pancreatic Cancer Clinical Trials. 2016

Matrisian, Lynn M / Berlin, Jordan D. ·From the Pancreatic Cancer Action Network, Manhattan Beach, CA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN. ·Am Soc Clin Oncol Educ Book · Pubmed #27249725.

ABSTRACT: Upper gastrointestinal malignancies comprise half of the deadliest cancers as defined by those with a 5-year survival rate less than 50%. Using pancreatic adenocarcinoma (PAC) as an example, we retrospectively evaluated the success of phase III clinical trials, examined the current landscape of clinical trials, and identified emerging areas that foretell the future for this disease. Pancreatic and liver cancers are on the rise and will be the second and third leading causes of cancer deaths in 2030. A total of 35 different agents or combinations have been tested in randomized phase III clinical trials for patients with advanced PAC over the past 25 years, but only 11% have been incorporated into clinical practice. There has been a 37% increase in the number of PAC trials open in the United States between 2011 to 2012 and 2014 to 2015. Enrollment has also increased slightly, from 3.85% of the newly diagnosed cases in 2011 to 4.15% in 2014. However, the demand for patients far exceeds the number of patients available for these trials. On the horizon is the realization that stratification of patients with PAC using biomarkers that predict a high probability of a response could reallocate patients to faster, smaller trials with a greater chance of a survival benefit. The current landscape of PAC clinical trials and the launch of the Pancreatic Cancer Action Network's Know Your Tumor initiative indicate this shift is starting to occur, with particular emphasis on targeted therapies, immunotherapies, and agents that disrupt the stroma.

12 Review Treatment of metastatic pancreatic adenocarcinoma: a review. 2014

Thota, Ramya / Pauff, James M / Berlin, Jordan D. · ·Oncology (Williston Park) · Pubmed #24683721.

ABSTRACT: Gemcitabine monotherapy has been the standard of care for patients with metastatic pancreatic cancer for several decades. Despite recent advances in various chemotherapeutic regimens and in the development of targeted therapies, metastatic pancreatic cancer remains highly resistant to chemotherapy. Previous studies of several combination regimens showed minimal or no significant change in overall survival compared with gemcitabine alone. Secreted protein acidic and rich in cysteine (SPARC) overexpression in pancreatic stromal fibroblasts is considered one of the major causes of chemotherapy resistance. The nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) has been found to be superior to other formulations of paclitaxel because of its favorable pharmacokinetic properties. Initial preclinical studies showed its synergistic effect with gemcitabine in pancreatic cancer, in which nab-paclitaxel is sequestered by SPARC to cause stromal depletion and increasing microvasculature, resulting in higher gemcitabine concentration within the tumor. In the recent phase III multinational Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), the combination of gemcitabine and nab-paclitaxel was shown to be superior to gemcitabine monotherapy, with an increase in median survival of 1.8 months. Combination therapy with gemcitabine plus erlotinib, or with gemcitabine plus nab-paclitaxel, or the multidrug regimen of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) can be considered as first-line chemotherapy for patients with metastatic pancreatic cancer. In this review we will discuss details of the recently approved combination of gemcitabine and nab-paclitaxel for first-line treatment of metastatic pancreatic adenocarcinoma and compare it with other therapeutic options.

13 Review Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. 2013

Katz, Matthew H G / Marsh, Robert / Herman, Joseph M / Shi, Qian / Collison, Eric / Venook, Alan P / Kindler, Hedy L / Alberts, Steven R / Philip, Philip / Lowy, Andrew M / Pisters, Peter W T / Posner, Mitchell C / Berlin, Jordan D / Ahmad, Syed A. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhgkatz@mdanderson.org ·Ann Surg Oncol · Pubmed #23435609.

ABSTRACT: BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

14 Review Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. 2013

Tempero, Margaret A / Klimstra, David / Berlin, Jordan / Hollingsworth, Tony / Kim, Paula / Merchant, Nipun / Moore, Malcolm / Pleskow, Doug / Wang-Gillam, Andrea / Lowy, Andrew M. ·Pancreas Center, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. mtempero@medicine.ucsf.edu ·Clin Cancer Res · Pubmed #23344262.

ABSTRACT: Pancreatic ductal adenocarcinoma is the most aggressive of all epithelial malignancies. In contrast to the favorable trends seen in most other common malignancies, the five-year survival of patients with this disease remains only 6%, a statistic that has changed minimally for decades. Only two drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in the last 15 years, and there are no established strategies for early detection.

15 Review Current treatment options for pancreatic carcinoma. 2011

Castellanos, Emily / Berlin, Jordan / Cardin, Dana Backlund. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. ·Curr Oncol Rep · Pubmed #21491194.

ABSTRACT: Pancreas cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers such as CA 19-9, are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing. This article reviews current strategies in the diagnosis and treatment of resectable and advanced pancreas cancer.

16 Review Treatment of early-stage pancreatic cancer. 2011

Castellanos, Emily H / Cardin, Dana B / Berlin, Jordan D. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6307, USA. ·Oncology (Williston Park) · Pubmed #21456390.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death, and it is estimated that over 43,000 people would be diagnosed with and over 36,000 people would die of pancreatic cancer in the United States in 2010. Surgical resection remains the only chance for possible cure, but only 15% to 20% of patients newly diagnosed with pancreatic cancer are considered for surgical resection. Of these, the median five-year survival rate is still less than 20%, with most resections resulting in recurrent disease. This suggests that even seemingly resectable pancreatic cancer has microscopic systemic spread before operative intervention occurs. Both adjuvant and neoadjuvant therapies have been studied in an effort to improve survival for patients with resectable pancreatic cancer.

17 Review Pancreatic cancer treatment and research: an international expert panel discussion. 2011

Tempero, M A / Berlin, J / Ducreux, M / Haller, D / Harper, P / Khayat, D / Schmoll, H-J / Sobrero, A / Van Cutsem, E. ·Division of Hematology/Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, USA. mtempero@medicine.ucsf.edu ·Ann Oncol · Pubmed #21199884.

ABSTRACT: BACKGROUND: Pancreatic cancer has proven extremely challenging to treat. A collaborative effort is needed to advance research and improve treatment. An expert conference was conducted to elicit perspectives regarding the current treatment and future research of pancreatic cancer. METHODS: The conference comprised an international panel of experts representing five European countries and the United States. RESULTS: Adjuvant radiotherapy is used more frequently in the United States than in Europe. In locally advanced disease, there is now more emphasis on early chemotherapy in both Europe and the United States. In metastatic disease, combination chemotherapy is commonly used in Europe and the United States. This varies by country. Advancing pancreatic research will require improving biorepositories and developing a roadmap to prioritize therapeutic targets in different models. Small randomized phase II trials of both non-selected and enriched patient populations will help identify activity of new agents. Phase III trials should only be initiated in appropriate patients based on strong clinical and biological signals. Developing drugs in the adjuvant setting may be preferable to eliminate some of the challenges of drug development in the advanced disease setting. CONCLUSION: Progress in research combined with encouraging improvements from the past offer hope for the future of pancreatic cancer patients.

18 Review Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. 2009

Philip, Philip A / Mooney, Margaret / Jaffe, Deborah / Eckhardt, Gail / Moore, Malcolm / Meropol, Neal / Emens, Leisha / O'Reilly, Eileen / Korc, Murray / Ellis, Lee / Benedetti, Jacqueline / Rothenberg, Mace / Willett, Christopher / Tempero, Margaret / Lowy, Andrew / Abbruzzese, James / Simeone, Diane / Hingorani, Sunil / Berlin, Jordan / Tepper, Joel. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #19858397.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.

19 Clinical Trial An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204). 2018

Berlin, Jordan D / Feng, Yang / Catalano, Paul / Abbruzzese, James L / Philip, Philip A / McWilliams, Robert R / Lowy, Andrew M / Benson, Al B / Blackstock, A William. ·Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. ·Oncology · Pubmed #29040974.

ABSTRACT: OBJECTIVES: Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS: Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS: A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS: Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.

20 Clinical Trial Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results : A phase I clinical trial. 2018

Cardin, Dana B / Goff, Laura W / Chan, Emily / Whisenant, Jennifer G / Dan Ayers, G / Takebe, Naoko / Arlinghaus, Lori R / Yankeelov, Thomas E / Berlin, Jordan / Merchant, Nipun. ·Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. dana.cardin@vanderbilt.edu. · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. dana.cardin@vanderbilt.edu. · Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. · Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA. · Institute for Computational and Engineering Sciences, Departments of Biomedical Engineering and Diagnostic Medicine, Livestrong Cancer Institutes, University of Texas, Austin, TX, USA. · Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, USA. ·Invest New Drugs · Pubmed #28990119.

ABSTRACT: Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m

21 Clinical Trial Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. 2016

Chan, Emily / Arlinghaus, Lori R / Cardin, Dana B / Goff, Laura / Berlin, Jordan D / Parikh, Alexander / Abramson, Richard G / Yankeelov, Thomas E / Hiebert, Scott / Merchant, Nipun / Bhaskara, Srividya / Chakravarthy, Anuradha Bapsi. ·Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States. · Vanderbilt University Institute of Imaging Science, United States. · Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States; Vanderbilt University Institute of Imaging Science, United States; Departments of Radiology and Radiological Sciences, Biomedical Engineering, Physics, and Cancer Biology, Vanderbilt University, United States. · Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, UHealth - University of Miami Health System, United States. · Department of Radiation Oncology and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, United States. · Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States. Electronic address: bapsi.chak@vanderbilt.edu. ·Radiother Oncol · Pubmed #27106554.

ABSTRACT: BACKGROUND AND PURPOSE: This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer. MATERIAL AND METHODS: Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity. RESULTS: The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35). CONCLUSIONS: The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.

22 Clinical Trial A phase 1b study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: an Academic Oncology GI Cancer Consortium study. 2016

Cohen, Steven J / O'Neil, Bert H / Berlin, Jordan / Ames, Patricia / McKinley, Marti / Horan, Julie / Catalano, Patricia M / Davies, Angela / Weekes, Colin D / Leichman, Lawrence. ·Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. steven.cohen@fccc.edu. · Indiana University Simon Cancer Center, Indianapolis, IN, USA. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · Abrazo Community Health Network, Phoenix, AZ, USA. · Aptium Oncology, Criterium, Inc., Los Angeles, CA, USA. · Novella Clinical, Boulder, CO, USA. · Champions Oncology, Hackensack, NJ, USA. · University of Colorado School of Medicine, Aurora, CO, USA. · New York University, New York, NY, USA. ·Cancer Chemother Pharmacol · Pubmed #26886016.

ABSTRACT: PURPOSE: Addition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy. METHODS: In this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard "3 + 3" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals. RESULTS: Nineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3. CONCLUSION: The addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.

23 Clinical Trial Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel Plus Cetuximab for Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study. 2016

Burtness, Barbara / Powell, Mark / Catalano, Paul / Berlin, Jordan / Liles, Darla K / Chapman, Andrew E / Mitchell, Edith / Benson, Al B. ·*Department of Medical Oncology, Fox Chase Cancer Center ∥Department of Internal Medicine, Thomas Jefferson University School of Medicine, Philadelphia, PA †Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA ‡Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN §East Carolina University School of Medicine, Greenville, NC ¶Lurie Cancer Center, Northwestern University, Chicago, IL. ·Am J Clin Oncol · Pubmed #24685886.

ABSTRACT: OBJECTIVES: The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. PATIENTS AND METHODS: Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m) and irinotecan (50 mg/m) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. RESULTS: A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. CONCLUSIONS: Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer.

24 Clinical Trial A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. 2015

O'Neil, B H / Scott, A J / Ma, W W / Cohen, S J / Leichman, L / Aisner, D L / Menter, A R / Tejani, M A / Cho, J K / Granfortuna, J / Coveler, A L / Olowokure, O O / Baranda, J C / Cusnir, M / Phillip, P / Boles, J / Nazemzadeh, R / Rarick, M / Cohen, D J / Radford, J / Fehrenbacher, L / Bajaj, R / Bathini, V / Fanta, P / Berlin, J / McRee, A J / Maguire, R / Wilhelm, F / Maniar, M / Jimeno, A / Gomes, C L / Messersmith, W A. ·Simon Cancer Center, Indiana University School of Medicine, Indianapolis. · University of Colorado, Denver, Aurora. · Roswell Park Cancer Institute, Buffalo. · Fox Chase Cancer Center, Philadelphia. · Kaiser Permanente, Lone Tree. · University of Rochester Medical Center, Rochester. · Oncare Hawaii, Honolulu. · Cone Health Cancer Center, Greensboro. · University of Washington, Seattle. · University of Cincinnati Cancer Institute, Cincinnati. · University of Kansas Medical Center, Westwood. · Mount Sinai Medical Center, Miami Beach. · Karmanos Cancer Institute, Detroit. · Rex Cancer Center UNC Healthcare, Raleigh. · Carolinas Health Care, Charlotte. · Kaiser Permanante Northwest, Portland. · NYU Clinical Cancer Center, New York. · Hendersonville Hematology and Oncology at Pardee, Hendersonville. · Kaiser Permanante Medical Center, Vallejo. · McLeod Regional Medical Center, Florence. · University of Massachusetts Memorial, Worcester. · UCSD Moores Cancer Center, La Jolla. · Vanderbilt-Ingram Cancer Center, Nashville. · UNC Lineberger Comprehensive Cancer Center, Chapel Hill. · Onconova Therapeutics Inc., Newtown. · Oncology Consortia of Criterium Inc., Saratoga Springs, USA. · University of Colorado, Denver, Aurora wells.messersmith@ucdenver.edu. ·Ann Oncol · Pubmed #26091808.

ABSTRACT: BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

25 Clinical Trial Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer. 2014

Cardin, Dana B / Goff, Laura / Li, Chung-I / Shyr, Yu / Winkler, Charles / DeVore, Russell / Schlabach, Larry / Holloway, Melanie / McClanahan, Pam / Meyer, Krista / Grigorieva, Julia / Berlin, Jordan / Chan, Emily. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. ·Cancer Med · Pubmed #24574334.

ABSTRACT: This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival (PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios (HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval (CI): 0.32-0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat "Good" patients had superior PFS (HR = 0.18, 95% CI: 0.06-0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13-0.77, P = 0.008) compared to VeriStrat "Poor" patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies.

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